Process for affecting the setting and working time of bioresorbable calcium phosphate cements

ABSTRACT

A fast-setting, bioresorbable calcium phosphate cement is prepared by a process which can be carried out with a heat treatment up to 1000° C. on a mixture of a wetting solution and a calcium phosphate powder having a Ca to P molar ratio of 0.5-2.5. The wetting solution suitable for use in the process of the present invention includes water, an organic solvent, an acidic and basic solution. A setting solution for mixing with the heated powder to form the fast-setting, bioresorbable calcium phosphate cement may be water, an acidic or basic solution according to the process of the present invention.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application is a continuation-in-part application of U.S.patent application Ser. No. 09/615,384, filed Jul. 13, 2000, which iscontinuation-in-part application of U.S. patent application Ser. No.09/351,912, filed Jul. 14, 1999, now U.S. Pat. No. 6,379,453B1. Theabove-listed applications are commonly assigned with the presentinvention and the entire contents of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for producing fast-setting,bioresorbable calcium phosphate cements (CPC), and in particular, to aprocess including a pre-heat treatment step to generate whiskers or finecrystals on surfaces of the CPC particles.

2. Description of the Related Art

U.S. Pat. No. 6,379,453B1 which is commonly assigned with the presentinvention discloses a process for producing a fast-setting,bioresorbable calcium phosphate cement comprising the following steps:obtaining a powder mixture from at least one calcium phosphate selectedfrom the group consisting of Ca₄(PO₄)₂O, CaHPO4.2H₂O, CaHPO₄,Ca₈H₂(PO₄)₆.5H2O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂, Ca₂P₂O₇, Ca₂H₂P₂O,wherein the molar ratio of Ca to P in the mixture is roughly between 1and 2; mixing the powder mixture in a phosphate-containing solution toobtain a powder/solution mixture having a concentration of less than 4 gpowder mixture per ml solution; immediately heating the powder/solutionmixture to a temperature of roughly 50° C. to 350° C. to obtain a powdercontaining uniformly distributed submicron-sized apatite crystals; andmixing the apatite crystal-containing powder in a phosphateion-containing solution to obtain a fast-setting, bioresorbable calciumphosphate cement.

SUMMARY OF THE INVENTION

An extensive study on the preparation of the fast-setting, bioresorbablecalcium phosphate cement disclosed in U.S. Pat. No. 6,379,453B1 has beenconducted by the same inventors and their co-workers, and found that thefast-setting, bioresorbable calcium phosphate cement can be preparedunder various conditions. Therefore an object of the invention is toprovide a more comprehensive process for producing a fast-setting,bioresorbable calcium phosphate cement.

The invention accomplishes the above object by providing a process whichcan be carried out with a heat treatment up to 1000° C. on a mixture ofa wetting solution and a calcium phosphate powder having a Ca to P molarratio of 0.5-2.5. The wetting solution suitable for use in the processof the present invention includes water, an organic solvent, an acidicand basic solution, not limited to the phosphate-containing solution. Asetting solution for mixing with the heated powder to form thefast-setting, bioresorbable calcium phosphate cement may be an acidicsolution, a basic solution or substantially pure water according to theprocess of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The preferred embodiments of the present invention include (but notlimited to) the following:

1) A process for producing a fast-setting, bioresorbable calciumphosphate cement, comprising the following steps:

(a) obtaining a calcium phosphate powder comprising at least one calciumphosphate selected from the group consisting of Ca₄(PO₄)₂O, CaHPO₄.2H₂O,CaHPO₄, Ca₈H₂(PO₄)₆.5H₂O, alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂, Ca₂P₂O₇,Ca₂H₂P₂O₈, wherein the molar ratio of Ca to P in said calcium phosphatepowder is between about 0.5 and 2.5;

(b) mixing said calcium phosphate powder obtained from step (a) with awetting solution to obtain a powder/solution mixture in a ratio of lessthan about 10 g powder per ml solution;

(c) heating the powder/solution mixture resulting from step (b) to atemperature up to about 1000° C. and

(d) mixing the resulting dried powder from step (c) in a settingsolution to obtain the fast-setting, bioresorbable calcium phosphatecement.

2) The process as set forth in item 1), wherein said Ca/P molar ratio instep (a) is between 1.0 and 2.0.

3) The process as set forth in item 2), wherein in step (d) theresulting dried powder from step (c) together with at least one additiveselected from the group of sodium phosphate (Na₃PO₄), disodium hydrogenphosphate (Na₂HPO₄), sodium dihydrogen phosphate (NaH₂PO₄), disodiumhydrogen phosphate dodecahydrate (Na₂HPO₄.12H₂O), disodium hydrogenphosphate heptahydrate (Na₂HPO₄.7H₂O), sodium phosphate dodecahydrate(Na₃PO₄.12H₂O), orthophosphoric acid (H₃PO₄), calcium sulfate (CaSO₄),Ca₄(PO₄)₂O, CaHPO₄.2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆.5H₂O, alpha-Ca₃(PO₄)₂,beta-Ca₃(PO₄)₂, Ca₂P₂O₇, and Ca₂H₂P₂O₈, are mixed with the settingsolution to obtain the fast-setting, bioresorbable calcium phosphatecement.

4) The process as set forth in item 3), wherein said wetting solution instep (b) is an acidic aqueous solution, a basic aqueous solution, anorganic solvent, or substantially pure water.

5) The process as set forth in item 4), wherein the organic solvent isethanol.

6) The process as set forth in item 1), wherein the mixing ratio in step(b) is less than about 5 g powder per ml solution.

7) The process as set forth in item 1), wherein the heating temperaturein step (c) is up to about 500° C.

8) The process as set forth in item 1), wherein the setting solution instep (d) is an acidic aqueous solution, a basic aqueous solution, or asubstantially pure water.

9) The process as set forth in item 4) or 8), wherein the acidic aqueoussolution is selected from the group consisting of nitric acid-3-(HNO₃),hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid (H₂CO₃),sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphatemonohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogenphosphate (KH₂PO₄), ammonium dihydrogen.phosphate (NH₄H₂PO₄), malicacid, acetic acid, lactic acid, citric acid, malonic acid, succinicacid, glutaric acid, tartaric acid, oxalic acid and their mixture.

10) The process as set forth in item 4) or 8), wherein the basic aqueoussolution is selected from the group consisting of ammonia, ammoniumhydroxide, alkali metal hydroxide, alkali earth hydroxide, disodiumhydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate,disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate(Na₃PO₄.12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassiumphosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO₄),ammonium phosphate trihydrate ((NH₄)₃PO₄.3H₂O), sodium bicarbonate(NaHCO₃), and their mixture.

11) The process as set forth in item 1) further comprising grinding theresulting dried powder from step (c) between step (c) and step (d).

12) The process as set forth in item 1), wherein the fast-setting,bioresorbable calcium phosphate cement obtained from step (d) has aviscosity so that it can be injected by a syringe.

The following examples are intended to demonstrate the invention morefully without acting as a limitation upon its scope, since numerousmodifications and variations will be apparent to those skilled in thisart.

EXAMPLE 1

To fabricate the CPC, the TTCP (Ca₄(PO₄)₂O) powder was prepared from thereaction of dicalcium pyrophosphate (Ca₂P₂O₇) (Sigma Chem. Co., StLouis, Mo., USA) and calcium carbonate (CaCO₃) (Katayama Chem. Co.,Tokyo, Japan) using the method suggested by Brown and Epstein [Journalof Research of the National Bureau of Standards—A Physics and Chemistry6 (1965) 69A 12], while the DCPA (CaHPO.sub.4) powder is a commercialproduct (Jassen Chemical Co., Japan).

5 g of a mixed powder of DCPA and TTCP in 1:1 molar ratio and 1.6 ml ofa wetting solution of a phosphoric acid aqueous solution having a pH of1.96 were mixed, and stirred for one minute. The resulting mixture wasplaced into an oven at 50° C. for 15 minutes, and the resulting driedmixture was mechanically ground for 20 minutes to fine particles afterbeing removed from the oven. 1 g of the fine particles and 0.4 ml ofphosphate aqueous solution (1.0 M, pH=6.0) were mixed to form a paste,which was tested every 30 seconds to determine the working time and thesetting time. The setting time is the time required when a 1 mm diameterpin with a load of ¼ pounds can be inserted only 1 mm deep into thesurface of the paste. The working time is the time after which the pasteis too viscous to be stirred. The working time of the paste of thisexample is 6.5 minutes and the setting time thereof is 11.5 minutes.

The paste was placed in a relatively large amount of deionized waterimmediately following the formation thereof, and it was observed thatthe paste was non-dispersive in deionized water.

EXAMPLES 2-5

The procedures of Example 1 were repeated except that the heat treatmentat 50° C. for 15 minutes was changed according to the conditions listedin Table 1. The performance is also listed in Table 1. TABLE 1Controlling Setting/working time treatment (min) Dispersive in water Ex.1 Heating, 50° C. 11.5/6.5 No Ex. 2 Heating, 100° C. 13.5/8.0 No Ex. 3Heating, 150° C.  8.5/8.0 No Ex. 4 Heating, 500° C.  2.5/1.5 No Ex. 5Heating, 1000° C.  35/31 No

EXAMPLES 6-10

The procedures of Example 1 were repeated by using the calcium phosphatepowders and the wetting solutions listed in Table 2. The performance isalso listed in Table 2. TABLE 2 Calcium Setting/ phosphate Wettingworking time Dispersive powder solution (min) in water Ex. 6 TCPPhosphoric 10/6.5 No acid Ex. 7 TCP Ethanol 12.5/8.5   No Ex. 8 TTCP +DCPA Phosphoric 11/8   No acid Ex. 9 TTCP + Phosphoric — No DCPA + TCPacid Ex. 10 DCPA + TCP Phosphoric 29/24  No acid

EXAMPLES 11-22

The procedures of Example 1 were repeated by using the wetting solutionshaving different pH values listed in Table 3. The performance is alsolisted in Table 3. TABLE 3 Dispersive Wetting solution pH in water Ex.11 Phosphoric acid 0.56 No Ex. 12 Phosphoric acid 1.03 No Ex. 13Phosphoric acid 1.17 No Ex. 14 Phosphoric acid 1.22 No Ex. 15 Phosphoricacid 1.32 No Ex. 16 Phosphoric acid 2.0 No Ex. 17 Acetic acid + 7.0 Nosodium carbonate Ex. 18 Sodium hydroxide 9.5 No Ex. 19 Sodium hydroxide12.55 No Ex. 20 Acetic acid 1.96 No Ex. 21 Ethanol — No Ex. 22 Deionizedwater 7.0 No

In the following examples, different setting solutions were used toverify the effect of the setting solution on the non-dispersive propertyof the calcium phosphate cement.

EXAMPLES 23-30

5 g of a mixed powder of DCPA and TTCP in 1:1 molar ratio and 1.6 ml ofa wetting solution of 25 mM phosphoric acid aqueous solution were mixed,and stirred for one minute. The resulting mixture was placed into anoven at 50° C. for 15 minutes, and the resulting dried mixture wasmechanically ground for 20 minutes to fine particles after being removedfrom the oven. 1 g of the fine particles and 0.4 ml of the settingsolutions listed in Table 4 were mixed to form a past, which was testedevery 30 seconds to determine the working time and the setting time asdefined in Example 1. The results are shown in Table 4.

EXAMPLES 31-33

The procedures of Example 23 were repeated except that an additive asshown in Table 4 was added to the mixed powder of DCPA and TTCP in aweight ratio of 1:10 after the mixed powder was removed from the oven,and the setting solution used in these examples was deionized water. Theresults are shown in Table 4.

EXAMPLES 34-45

To 5 g TTCP powder which was used as synthesized 10 ml of 1M phosphoricacid aqueous solution was poured, and the mixture was filteredimmediately. The filtered cake was placed into an oven at 150° C. for 10minutes, and the resulting dried mixture was mechanically ground for 5hours to fine particles. The resulting heat-treated TTCP fine particlesand the TTCP powder as synthesized (without heat treatment) were mixedin a weight ratio of 1:1. 1 g of the mixed TTCP powder and 0.4 ml of thesetting solutions listed in Table 4 were mixed to form a paste, whichwas tested every 30 seconds to determine the working time and thesetting time as defined in Example 1. The results are shown in Table 4.TABLE 4 Setting Dispersive Powder solution pH in water Ex. 23 TTCP +DCPA 25 mM H₃PO₄ 1.96 No Ex. 24 TTCP + DCPA Acetic acid — No Ex. 25TTCP + DCPA HNO₃ — No Ex. 26 TTCP + DCPA HCl — No Ex. 27 TTCP + DCPA(NH4)HPO₄ 7.96 No 13.0/8.0  Ex. 28 TTCP + DCPA K₂HPO₄ 8.76 No 31.0/23.5Ex. 29 TTCP + DCPA NaOH 13.57 No 28.0/19.0 Ex. 30 TTCP + DCPA Deionized7.0 No water Ex. 31 TTCP + DCPA + Deionized 7.0 No phosphoric acid waterEx. 32 TTCP + DCPA + Deionized 7.0 No 20.5/16.5 NaH₂PO₄.2H₂O water Ex.33 TTCP + DCPA + Deionized 7.0 No 11.0/7.0  Na₂HPO₄.2H₂O water Ex. 34TTCP Deionized 7.0 No 35.0/31.0 water Ex. 35 TTCP 3M H₃PO₄ −0.7 No17.5/16.0 Ex. 36 TTCP HCl −1.53 No Ex. 37 TTCP HCl −0.83 No 22.5/17.5Ex. 38 TTCP HNO₃ −1.53 No Ex. 39 TTCP HNO₃ −0.83 No   33/28.5 Ex. 40TTCP HNO₃ 0 No 27.5/22.0 Ex. 41 TTCP HNO₃ 2 No 20.5/16.0 Ex. 42 TTCPK₂HPO₄ 8.76 No 9.0/7.5 Ex. 43 TTCP (NH₄)₂HPO₄ 7.96 No 8.5/6.5 Ex. 44TTCP CH₃COOH No 4.5/3.5 Ex. 45 TTCP NaOH 13.57 No 52/30

Although the present invention has been described with reference tospecific details of certain embodiments thereof, it is not intended thatsuch details should be regarded as limitations upon the scope of theinvention except as and to the extent that they are included in theaccompanying claims. Many modifications and variations are possible inlight of the above disclosure.

1. A process for producing a fast-setting, bioresorbable calciumphosphate cement, comprising the following steps: (a) obtaining acalcium phosphate powder comprising at least one calcium phosphateselected from the group consisting of Ca4(PO4)2O, CaHPO4.2H2O, CaHPO4,Ca8H2(PO4)6.5H2O, alpha-Ca3(PO4)2, beta-Ca3(PO4)2, Ca2P2O7, Ca2H2P2O8,wherein the molar ration of Ca to P in said calcium phosphate powder isbetween about 0.5 and 2.5; (b) mixing said calcium phosphate powderobtained from step (a) with a wetting solution to obtain apowder/solution mixture in a ratio of less than about 10 g powder per mlsolution; (c) heating the powder/solution mixture resulting from step(b) to a temperature greater than room temperature up to about 1000° C.;and (d) mixing the resulting dried powder from step (c) in a settingsolution to obtain the fast-setting, bioresorbable calcium phosphatecement.
 2. The process as set forth in claim 1, wherein said Ca/P molarratio in step (a) is between 1.0 and 2.0.
 3. The process as set forth inclaim 1, wherein in step (d) the resulting dried powder from step (c)together with at least one additive selected from the group of Na3PO4,Na2HPO4, NaH2PO4, Na2HPO4.12H2O, Na2HPO4.7H2O, H3PO4.12H2O, H3PO4,CaSO4, Ca4(PO4)2O, CaHPO4.2H2O, CaHPO4, Ca8H2(PO4)6.5H2O,alpha-Ca3(PO4)2-, beta-Ca3(PO4)2, Ca2P2O7, and Ca2H2P2O8, are mixed withthe setting solution to obtain the fast-setting, bioresorbable calciumphosphate cement.
 4. The process as set forth in claim 1, wherein saidwetting solution in step (b) is an acidic aqueous solution, a basicaqueous solution, an organic solvent, or substantially pure water. 5.The process as set forth in claim 4, wherein the acidic aqueous solutionis selected from the group consisting of nitric acid, hydrochloric acid,phosphoric acid, carbonic acid, sodium dihydrogen phosphate, sodiumdihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate,potassium dihydrogen phosphate, ammonium dihydrogen.phosphate, malicacid, acetic acid, lactic acid, citric acid, malonic acid, succinicacid, glutaric acid, tartaric acid, oxalic acid and their mixture. 6.The process as set forth in claim 4, wherein the basic aqueous solutionis selected from the group consisting of ammonia, ammonium hydroxide,alkali metal hydroxide, alkaline earth hydroxide, disodium hydrogenphosphate, disodium hydrogen phosphate dodecahydrate, disodium hydrogenphosphate heptahydrate, sodium phosphate dodecahydrate, dipotassiumhydrogen phosphate, potassium phosphate tribasic, diammonium hydrogenphosphate, ammonium phosphate trihydrate, sodium bicarbonate, and theirmixture.
 7. The process as set forth in claim 4, wherein the organicsolvent is ethanol.
 8. The process as set forth in claim 1, wherein themixing ratio in step (b) is less than about 5 g powder per ml solution.9. The process as set forth in claim 1, wherein the heating temperaturein step (c) is greater than room temperature up to about 500° C.
 10. Theprocess as set forth in claim 1, wherein the setting solution in step(d) is an acidic aqueous solution, a basic aqueous solution, orsubstantially pure water.
 11. The process as set forth in claim 10,wherein the acidic aqueous solution is selected from the groupconsisting of nitric acid, hydrochloric acid, phosphoric acid, carbonicacid, sodium dihydrogen phosphate, sodium dihydrogen phosphatemonohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogenphosphate, ammonium dihydrogen.phosphate, malic acid, acetic acid,lactic acid, citric acid, malonic acid, succinic acid, glutaric acid,tartaric acid, oxalic acid and their mixture.
 12. The process as setforth in claim 10, wherein the basic aqueous solution is selected fromthe group consisting of ammonia, ammonium hydroxide, alkali metalhydroxide, alkaline earth hydroxide, disodium hydrogen phosphate,disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphateheptahydrate, sodium phosphate dodecahydrate, dipotassium hydrogenphosphate, potassium phosphate tribasic, diammonium hydrogen phosphate,ammonium phosphate trihydrate, sodium bicarbonate, and their mixture.13. The process as set forth in claim 1 further comprising grinding theresulting dried powder from step (c) between step (c) and step (d). 14.The process as set forth in claim 1, wherein the fast-setting,bioresorbable calcium phosphate cement obtained from step (d) has aviscosity so that it can be injected by a syringe.